Diabetes mellitus is a group of endocrine and metabolic syndromes of disordered metabolisms of carbohydrates, proteins, fats, water and electrolytes in the body caused by reduced insulin secretion or defects in insulin function resulting from combined action of a variety of genetic and environmental factors. It is characterized by chronic increase in blood glucose level, and leads to chronic complications of the eyes, kidneys, liver and other organs after a long illness. Diabetes mellitus itself and its complications seriously endanger human health, and the treatment of diabetes mellitus and its complications has become a major global public health problem.
Diabetic retinopathy is the most common diabetic eye disease, and often leads to diminution of vision or blindness. According to statistics, 50% of diabetics will have this disease in about 10 years of the disease course, and the figure will reach up to 80% in 15 years or more. The more severe the condition of diabetes mellitus is, the older the patient is, the higher the incidence of the disease is.
Plasmin is a key component of the plasminogen activation system (PA system). It is a broad-spectrum protease that can hydrolyze several components of the extracellular matrix (ECM), including fibrin, gelatin, fibronectin, laminin, and proteoglycan [1]. In addition, plasmin can activate some pro-matrix metalloproteinases (pro-MMPs) to form active matrix metalloproteinases (MMPs). Therefore, plasmin is considered to be an important upstream regulator of extracellular proteolysis [2,3]. Plasmin is formed by proteolysis of plasminogen by two physiological PAs: tissue plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA). Due to the relatively high level of plasminogen in plasma and other body fluids, it is traditionally believed that the regulation of the PA system is primarily achieved through the levels of PA synthesis and activity. The synthesis of PA system components is strictly regulated by different factors, such as hormones, growth factors and cytokines. In addition, there are also specific physiological inhibitors of plasmin and PAs. The main inhibitor of plasmin is α2-antiplasmin. There are uPA-specific cell surface receptors (uPARs) that have direct hydrolytic activity on certain cell surfaces [4,5].
Plasminogen (plg) is a single-stranded glycoprotein with a molecular weight of about 92 kDa [6,7]. Plasminogen is mainly synthesized in the liver and is abundantly present in the extracellular fluid. The content of plasminogen in plasma is about 2 μM. Therefore, plasminogen is a huge potential source of proteolytic activity in tissues and body fluids [8,9]. Plasminogen exists in two molecular forms: glutamic acid-plasminogen (Glu-plasminogen) and lysine-plasminogen (Lys-plasminogen). The naturally secreted and uncleaved forms of plasminogen have an amino-terminal (N-terminal) glutamic acid and are therefore referred to as glutamic acid-plasminogen. However, in the presence of plasmin, glutamic acid-plasminogen is hydrolyzed to lysine-plasminogen at Lys76-Lys77. Compared with glutamic acid-plasminogen, lysine-plasminogen has a higher affinity for fibrin and can be activated by PAs at a higher rate. The Arg560-Val561 peptide bond between these two forms of plasminogen can be cleaved by uPA or tPA, resulting in the formation of plasmin as a disulfide-linked double-strand protease [10]. The amino-terminal portion of plasminogen contains five homotrimeric rings, i.e., the so-called kringles, and the carboxy-terminal portion contains a protease domain. Some kringles contain lysine-binding sites that mediate the specific interaction of plasminogen with fibrin and its inhibitor α2-AP. A newly discovered 38 kDa of plasminogen is a fragment comprising kringles 1-4, is a potent inhibitor of angiogenesis. This fragment is named as angiostatin and can be produced by the proteolysis of plasminogen via several proteases.
The main substrate of plasmin is fibrin, and the dissolution of fibrin is the key to prevent pathological thrombosis [11]. Plasmin also has substrate specificity for several components of ECM, including laminin, fibronectin, proteoglycan and gelatin, indicating that plasmin also plays an important role in ECM remodeling [7,12,13]. Indirectly, plasmin can also degrade other components of ECM by converting certain protease precursors into active proteases, including MMP-1, MMP-2, MMP-3 and MMP-9. Therefore, it has been proposed that plasmin may be an important upstream regulator of extracellular proteolysis [14]. In addition, plasmin has the ability to activate certain potential forms of growth factors [15-17]. In vitro, plasmin can also hydrolyze components of the complement system and release chemotactic complement fragments.
The existing treatment method mainly includes basic treatment, namely, auxiliary treatment which is carried out for eye disorders through regular eye examination on the basis of the blood glucose control. We have surprisingly found with spontaneous diabetic mice as research objects that plasminogen and/or plasmin has a good therapeutic effect and high safety in the inhibition of tissue injuries of internal organs, blood vessels, nerves, and the retina and in the prevention or treatment of diabetic retinopathy. Therefore, plasminogen may become a new strategy for treating diabetes mellitus complications including retinopathy.